CHEM E-120 Harvard University Extension School

CHEM E-120Harvard University Extension School

Neurodegenerative DisordersAlzheimer’s Disease

April 6, 2011

14/6/11 CHEM E-120

Alzheimer’s DiseaseMost prevalent of the neurodegenerative diseasesAffects ~ 15-20 million individuals worldwideAge onset ~ 60 – 65 years, risk of developing Alzheimer’s doubles every 5 years after age 65 with a 50% chance after age 85.8th leading cause of death

Main clinical symptom is dementia

early memory impairmentepisodic memoryprogressive decline in executive function – reasoning, etcdrastic alterations in personality – aggressive behavior

DSM-IV classifies several forms of dementiaNo diagnostic tool premortem except clinical dementia rating (CDR)

Postmortem analysis is characterized by the identification of neurofibrillary tangles (NFT) and amyloid plaques.

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Cholinergic Hypothesis - AD

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Based on finding reduced activity of choline acetyltransferase activity and loss of cholinergic neurons in the forebrain. Reduction in amount of acetylcholine.

Cholinergic system appears important in

cognitive function: attention, memorynoncognitive function: depression, psychosis, aggression, sleep

Acetylcholine (ACh) binds to muscarinic receptors and nicotinic (nAChR) Na+ channels.

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HON

Choline

choline acetyltransferase

acetyl-S-CoA ON

O

acetylcholine

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Neurotransmitters - Acetylcholine

mnemonic functionneurofibrally tanglesappear here firstin early satge AD

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Loss of ACh

How to increase it?

1. Inhibition of ACHE2. M1 agonist (stimulates cognitive function)3. NAChR agonists α4β2 agonist

predominate NACh subunit in brainpartial agonist Varenicline

(7)5 agonist inc Ca2+ permeabilityagonist increase cognition

4. 5-HT1A antagonist increase ACh and glutamate

Comprehensive Medicinal Chemistry IIChapter 6.084/6/11 CHEM E-120

Mediciation Development Alzheimer’s Disease

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1. Acetylcholineesterase inhibitors (4 approved for use)

Tacrine (Cognex)Donepezil (Aricept)Rivastigmine (Exelon)Galantamine (Razadyne, Reminyl)

2. NMDA noncompetitive antagonist (Approved)

Memantine (Namenda)reduces Ca2+ influx into neurons, excess Ca2+ is cytotoxic

3. β-Secretase inhibitors4. GSK-3 inhibitors (Annual Reports in Med. Chem. 2010, 44, 35. 5HT1A antagonists

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AcetylcholinesteraseAcetylcholinesterase (ACHE) is a serine esterase enzyme

ACHE has an anionic binding site which attracts the positively charged quaternary ammonium group of ACH. A serine then attacks and cleaves the ester. This is an example of general base catalysis.

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ON

O

NH

OO

O

Glu (E) 327

NH O

O H

HNO

NHN

His (H) 440

Ser (S) 200

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van der Waals surface map of acetylcholine in active site of AChE

Phe297

Phe295

vs aliphaticin BChE

catalytic triad

inhibitor binding site

Glu202 quat siteBasic Neurochemistry p. 1954/6/11 CHEM E-120

9Acta Biologica Hungarica 54 (2), pp. 183–189 (2003)4/6/11 CHEM E-120

Donepezil - Aricept

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Approved in 1997

Annual Reports in Medicinal Chemistry 1998, 33, 332Jpn. J. Pharmacol. 89, 7 – 20 (2002)

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Discovery of Donepezil

Jpn. J. Pharmacol. 89, 7 – 20 (2002)

1 found through random screeningprepared about 700 analogs

benzylpiperizine to benzylpiperidine

replacement of ether

4 poor bioavailability and short durationof action

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7 replace amide by ketone

6 cyclic amide better inhibitionthan 5

leads to 8IC50 less than 4 but longer duration of action

SAR

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ring size

carbonyl

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p-methoxy4/6/11 CHEM E-120

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location and number of N’s

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pKa!

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oral ID50 = 2.6 mg/kg

Tacrine oral ID50 = 9.5 mg/kg

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equivalent to Meynert nucleus in humans

move from light to dark chamber (foot shock)learn: avoid dark chamber

no le

arni

ng

MS cholinergic projections to hippocampus

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Discovery of DonepezilResult of J-CGIC

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Structure March 1999, 7:297–307 π-π stacking

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Structure March 1999, 7:297–307

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Amyloid Plaque Formation

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Insoluble, neurotoxic, protein clusters formed from Amyloid Precursor Protein (APP)

770 AA AA669 Asp

BACE β-secretase

AA669AA770

Β-CFT

γ-secretase

Aβ – β-amyloid1-40(42)

AChEfibril

peripheral siteof AChE

N terminusextracellular

C terminusintracellular

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BACE Inhibitors 2-Amino-3,4-dihydroquinazolines

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J. Med. Chem. 2007, 50, 4261 Johnson & Johnson

High-throughput hit from a screen of their corporate compoundcollection

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BACE - 2-Amino-3,4-dihydroquinazolines

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First obtained a X-ray crystal of 1 bound to BACE-1

1 forms a U shaped conformation in active site4/6/11 CHEM E-120

BACE - 2-Amino-3,4-dihydroquinazolines

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5-HT1A Antagonists

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It has been suggested that the serotonergic system may be hyperactive in AD as a result of enhanced turnover of serotonin. This will ultimately result in the reduction of activity of cortical pathways by the binding of serotonin to autoreceptors on presynaptic neurons.

It has been found that 5-HT1A antagonists can facilitate glutamatergic activity and cholinergic activity which leads to a reduction in cognitive deficits.

The Potential Utility of 5-HT1A Receptor Antagonists in the Treatment of Cognitive Dysfunction Associated with Alzheimer’s Disease Current Pharmaceutical Design, 2002, 8, 139-145

Lecozatan – Selective 5-HT1A Antagonist

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WAY100135 – Selective 5-HT1A Antagonist

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Arylpiperazines reported to be high-affinity 5-HT1A ligands (JMC 1988, 31, 1968)

Eur. J. Pharmacol. 1988, 154, 339

In 1993 WAY100135 was reported as the first true selective antagonist of 5-HT1A

Eur. J. Pharmacol. 1993, 237, 283

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WAY100135 – Selective 5-HT1A AntagonistEvidence for presynaptic antagonist activity (autoreceptor)

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Drug ID50 (μg/kg i.v.)

8-OH-DPAT (agonist) 1.9BMY7378 (partial agonist) 12NAN-190 (partial agonist) 16MDL73005EF (“) 81(±)WAY100135 >2500(+)WAY100135 >600 (-)WAY100135 >1000

serotonin at 5-HT1A presynaptic inhibits firing

inhibitory effect serotonin is blocked

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WAY100135 – Selective 5-HT1A AntagonistEvidence for presynaptic antagonist activity

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The 5-HT1A agonist 8-OH-DPAT induces hypothermia in mice.

An antagonist should prevent this in a dose-dependent manner

(±)WAY100135 ED50 = 2.0 mg/kg s.c.(+)WAY100135 ED50 = 1.5 mg/kg s.c. (-)WAY100135 ineffective up to 30 mg/kg

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WAY100135 – Selective 5-HT1A AntagonistEvidence for postsynaptic antagonist activity

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5-CT is a 5-HT1A

agonist that:

Inhibits the electricallystimulated contractionof muscle

rightward shift that isindicative of antagonism

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WAY100135 – Selective 5-HT1A AntagonistEvidence for postsynaptic antagonist activity

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The 8-OH-DPAT syndromeDue to 5-HT activation

Extended flat body postureForepaw treadingHyperlocomotion

(±)(+)

(-)

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WAY100635

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Eur. J. Pharmacol. 1995, 281, 81-88

Drug IC50 (nM) pA2 (5-CT) ED50 (antag. Induced hypothermia)

(±)WAY100135 34 7.2 2.5 mg/kg(+)WAY100135 15 (-)WAY100135 437

WAY100635 1.35 9.7 0.01 mg/kg

>100 fold selective vs other 5-HT receptors and 35 other receptors/transporters

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WAY-100635 lacked bioavailability.

Modification of the amide portion and N-phenyl portion.

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Though not the most potentin vitro antagonist, 11c showedmost potency in vivo

Rats trained to respond to fixed ratio-30 schedule offood presentation to receive afood pellet.

Agonist 8-OH-DPAT reducesresponse rate.

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J. Pharmacology and Experimental Therapeutics 2005, 314, 12744/6/11 CHEM E-120


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In vivo microdialysisin conscious rats

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Time dependent increase in glutamate levels in dentate gyrus by in vivo microdialysis

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Time dependent increase in acetylcholine levels in hippocampus by in vivo microdialysis

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Lecozotan enhances cognitive function in the aged rhesus monkey as assessed by DMTS(delayed matching-to-sample) performance efficiency.

16% @ 1.0 mg/kg

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Nature Clinical Pharmacology and Therapeutics 2008, 83, 86

binding of 11C-WAY-100635

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Nature Clinical pharmacology and Therapeutics 2008, 83, 86

Study shows Lecozotan is readily absorbed into the brain and binds to 5-HT1A receptors regardless of age and is not affected by AD being present

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CHEM E-120 Harvard University Extension School

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